Driven by the fact that the majority of key molecules in biological systems are chiral, and thus most enantiomers of drugs showcase marked differences in biological activities, the demand for the preparation of chiral compounds in enantiopure form is ever increasing. For this reason, the development of versatile and efficient synthetic tools for the construction of asymmetric building blocks is of paramount importance in current modern Organic Chemistry. One of the most efficient ways of enantioselectively constructing molecules is by asymmetric organometallic catalysis, where the unique reactivity of transition metals is exploited in the context of enantioselective reactions using appropriate chiral ligands. Since the level of enantiocontrol is largely determined by the ligand employed, the development of new chiral ligands is of utmost importance in the field of asymmetric synthesis.
By far, the most popular ligand for this purpose has been the 1,1′-Bi-2-naphthol (BINOL)-derived diphosphine (BINAP). This was established in the 80s by Nobel Laureate Ryoji Noyori as a remarkably efficient ligand for Rh and Ru-catalyzed asymmetric hydrogenations and was instrumental in popularizing the field of asymmetric organometallic catalysis. Being widely regarded as a privileged scaffold, BINAP has been used in countless unrelated reactions with excellent results. BINOL-derived ligands are not a panacea, however, as in many reactions their performance is unsatisfactory. For this reason, chemists in the field strive to develop new powerful and general ligands.
Acetal-containing ligands have been of great utility to asymmetric catalysis and several important scaffolds containing acetal functionality are depicted in FIG. 1. While the acetal functionality cannot withhold strongly acidic or Lewis acidic conditions, these functionalities are compatible with most of the reaction conditions traditionally employed in transition metal catalysis. Additionally, the presence of the oxygenation in the ligand backbone can affect the electronic and structural properties of the ligand, and the synthesis of such ligands could offer significant advantages over the preparation of similar carbon-substituted analogs. Not surprisingly, acetal-containing ligands are present in the list of products vendored by Strem (cf. FIG. 1) as well as other suppliers (Sigma, etc.).
In 1999, the synthesis of chiral 1,1-spirobiindane-7,7-diol (SPINOL, FIG. 1) was first reported by the Birman group. Following this, several derivatives were introduced in catalysis such as diphosphine ligands in 2003, and as phosphoric acids in 2010. Subsequently, the SPINOL core has been demonstrated to be exceptional in catalysis in many instances. However, despite the overwhelming success of the SPINOL scaffold, a major disadvantage of both SPINOL-derived catalysts and ligands, which explains their lack of popularity compared to other catalysts, is that their preparation is low yielding, costly, and involves a large number of steps, including a chiral resolution.